Association of MHTFR Ala222Val (rs1801133) polymorphism and breast cancer susceptibility: An update meta-analysis based on 51 research studies

  • Liwa Yu1 and

    Affiliated with

    • Jianqiu Chen1Email author

      Affiliated with

      Diagnostic Pathology20127:171

      DOI: 10.1186/1746-1596-7-171

      Received: 19 November 2012

      Accepted: 30 November 2012

      Published: 7 December 2012

      Abstract

      Background

      The association between MHTFR Ala222Val polymorphism and breast cancer (BC) risk are inconclusive. To derive a more precise estimation of the relationship, a systematic review and meta-analysis was performed.

      Methods

      A comprehensive search was conducted through researching MEDLINE, EMBASE, PubMed, Web of Science, Chinese Biomedical Literature database (CBM) and China National Knowledge Infrastructure (CNKI) databases before August 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association.

      Results

      A total of 51 studies including 20,907 cases and 23,905 controls were involved in this meta-analysis. Overall, significant associations were found between MTHFR Ala222Val polymorphism and BC risk when all studies pooled into the meta-analysis (Ala/Ala vs Val/Val: OR=0.870, 95%CI=0.789–0.958,P=0.005; Ala/Val vs Val/Val: OR=0.895, 95%CI=0.821–0.976, P=0.012; dominant model: OR=0.882, 95%CI=0.808–0.963, P=0.005; and recessive model: OR = 0.944, 95%CI=0.898–0.993, P=0.026; Ala allele vs Val allele: OR = 0.935, 95%CI=0.887–0.986, P=0.013). In the subgroup analysis by ethnicity, the same results were found in Asian populations, while no significant associations were found for all comparison models in other Ethnicity populations.

      Conclusion

      In conclusion, our meta-analysis provides the evidence that MTHFR Ala222Val gene polymorphisms contributed to the breast cancer development.

      Virtual slides

      The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1966146911851976

      Keywords

      Polymorphism Breast cancer MTFHR Ala222Val Meta-analysis

      Introduction

      Breast cancer is the most common cancer and the main cause of cancer mortality in women. The etiology towards to this disease is poorly understood, some risk factors including familial history of the disease, age of menarche and of menopause, diet, reproductive history, high estrogen exposure as well as genetic factors may contribute to its development [1, 2]. Studies suggest that the effect determined by low-penetrance genes, may provide a plausible explanation for BC susceptibility. Polymorphisms in genes are associated with a risk or protection against the disease. 5,10-methylenetetrahydrofolate reductase (MTHFR) is one important genes located at 1p36.3 [3]. MTHFR Ala222Val polymorphism has become the most commonly studied one, which has been considered to influence the enzyme activity of MTHFR[4]. The MTHFR 222Val/Val (homozygote) genotype results in 30% enzyme activity in vitro compared with the Ala/Ala wild-type [5]. Numerous epidemiological studies have evaluated the association between the MTHFR Ala222Val polymorphisms and BC risk. However, these studies have yielded conflicting results, partially because of the possible small effect of the polymorphism on BC risk and the relatively small sample size in each of published studies. The aim of this study is to derive a more precise estimation of these associations by performing this meta-analysis.

      Materials and methods

      Literature search

      All studies that examined the association between the MFTHR Ala222Val polymorphism and BC were identified. A comprehensive search was conducted through researching MEDLINE, EMBASE, PubMed, Web of Science, China Biomedical Literature database (CBM) and China National Knowledge Infrastructure (CNKI) databases before August 2012. The search strategy included the combination of “breast cancer,” “breast neoplasm,” “methylene-tetrahydrofolate reductase,” “MTHFR,” “Ala222Val”, “rs1801133”, “variant,” and “polymorphism.” References of the retrieved articles were also screened. Non-familial case–control studies were eligible if they determined the distribution for this polymorphism in unrelated patients with breast cancer and in a concurrent control group of healthy subjects using molecular methods for genotyping. Of the studies with the same or overlapping data by the same investigators, we selected the most recent ones with the most subjects. We evaluated all associated publications to retrieve the most eligible literatures. The reference lists of reviews and retrieved articles were hand searched at the same time. We did not include abstracts or unpublished reports. When overlapping data of the same patient population were included in more than one publication, only the most recent or complete study was used in this meta-analysis.

      Inclusion and exclusion criteria

      The following inclusion criteria were used to select literatures for the meta-analysis: (1) information on the evaluation of MFTHR Ala222Val polymorphism and BC susceptibility; (2)Only the cohort and case-control studies were considered;(3) sufficient genotype data were presented to calculate the OR with 95% CI. Major reasons for exclusion of studies were: (1) none-case–control studies; (2) reviews and duplication of the previous publication; (3) control population including malignant tumor patients; (4) no usable data reported.

      Data extraction

      Two investigators reviewed and extracted information from all eligible publications independently, according to the inclusion and exclusion criteria listed above. An agreement was reached by discussion between the two reviewers whenever there was a conflict. The following items were collected from each study: first author’s surname, year of publication, ethnicity, total number of cases and controls with Ala/Ala, Ala/Val, and Val/Val genotypes, respectively. Different descents were categorized as Caucasians, Asians, and Mixed populations which included more than one ethnic descent. For case–control studies, data were extracted separately for each group whenever possible.

      Statistical analysis

      The strength of the association between MFHTR Ala222Val polymorphism and BC risk was measured by ORs, whereas a sense of the precision of the estimate was given by 95% Cls. The significance of the summary OR was determined with a Z-test. We first examined MFHTR Ala222Val genotypes using co-dominant model (homogeneous co-dominant model: Ala/Ala vs Val/Val, heterogeneous co-dominant model: Ala/Val vs Val/Val), recessive (Ala/Ala vs Ala/Val + Val/Val), and dominant (Ala/Ala + Ala/Val vs Val/Val) genetic models. Then, the relationship between the allele and susceptibility to BC was examined (addictive model: Ala allele vs Val allele). Stratified analyses were also performed by ethnicities. A chi-square-based Q-statistic test and an I 2 -test test were both performed to evaluate the between-study heterogeneity of the studies.

      Two models including the fixed-effects model and the random-effects model of meta-analysis were applied for dichotomous outcomes. The fixed-effects model assumes that studies are sampled from populations with the same effect size, making an adjustment to the study weights according to the in-study variance. The random-effects model assumes that studies are taken from populations with varying effect sizes, calculating the study weights both from in-study and between-study variances, considering the extent of variation, or heterogeneity. A P-value ≥0.10 for the Q-test indicated lack of heterogeneity among the studies, and so the summary OR estimate of each study was calculated by the fixed-effects modelm [6]. Otherwise, the random-effects model (DerSimonian and Laird method) was used [7]. I 2 statistic can be used to quantify heterogeneity irrespective of the number of studies. The significance of the pooled OR was determined by the Z-test and P<0.05 was considered as statistically significant. Subgroup analyses were performed by ethnicity to explore the reasons of heterogeneity. Sensitivity analyses were performed to assess the stability of the results. To investigate whether publication bias might affect the validity of the estimates, funnel plot were constructed. An asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger’s linear regression test, a linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of OR. The significance of the intercept was determined by the t-test suggested by Egger (P<0.05 was considered representative of statistically significant publication bias). All statistical tests were performed with Stata (Version 12.0, Stata Corporation, College Station, TX), using two-sided P-values.

      Results

      Eligible studies

      51 eligible studies on MTHFR Ala222Val genotypes and colorectal cancer were identified through literature search and selection based on the inclusion and exclusion criteria [858]. The publishing year of the studies was from 2002 to 2012. There were 25 studies of Caucasian, 19 studies of Asians and 7 studies of Mixed populations. In total, 20,907 BC cases and 23,905 controls were included in the meta-analysis. The selected study characteristics were summarized in Table 1.
      Table 1

      The main characteristics of these studies and the distribution of MTHFR Ala222Val genotypes and alleles among cases and controls

      First author [Inference]

      Year

      Ethnicity

       

      Cases

        

      Controls

       

      HWE

      CC

      CT

      TT

      CC

      CT

      TT

      Sharp [8]

      2002

      Caucasian

      30

      19

      5

      25

      21

      11

      0.103

      Campbell [9]

      2002

      Caucasian

      140

      162

      33

      118

      92

      23

      0.420

      Semenza [10]

      2003

      Caucasian

      42

      58

      5

      112

      111

      24

      0.643

      Langsenlehner [11]

      2003

      Caucasian

      208

      222

      64

      215

      215

      65

      0.333

      Ergul [12]

      2003

      Caucasian

      60

      41

      17

      94

      87

      12

      0.164

      Shrubsole [13]

      2004

      Asian

      374

      555

      183

      387

      577

      196

      0.442

      Fo¨rsti [14]

      2004

      Caucasian

      134

      81

      8

      181

      104

      13

      0.689

      Lee [15]

      2004

      Asian

      58

      96

      32

      50

      80

      17

      0.076

      Grieu [16]

      2004

      Caucasian

      166

      141

      27

      242

      259

      50

      0.100

      Lin [17]

      2004

      Asian

      43

      38

      7

      173

      145

      24

      0.389

      Qi [18]

      2004

      Asian

      42

      104

      71

      59

      105

      54

      0.593

      Chen [19]

      2005

      Mixed

      398

      476

      189

      440

      509

      155

      0.689

      Kalemi [20]

      2005

      Caucasian

      19

      16

      7

      23

      20

      8

      0.313

      Deligezer [21]

      2005

      Caucasian

      98

      68

      23

      128

      83

      12

      0.759

      Justenhoven [22]

      2005

      Caucasian

      249

      247

      61

      261

      279

      93

      0.193

      Chou [23]

      2006

      Asian

      73

      51

      18

      132

      120

      33

      0.475

      Kalyankumar [24]

      2006

      Caucasian

      45

      37

      6

      61

      31

      3

      0.693

      Xu [25]

      2007

      Mixed

      398

      476

      189

      440

      509

      155

      0.689

      Hekim [26]

      2007

      Caucasian

      22

      16

      2

      38

      26

      4

      0.872

      Macis [27]

      2007

      Caucasian

      14

      20

      12

      28

      41

      11

      0.511

      Yu [28]

      2007

      Asian

      56

      54

      9

      225

      170

      25

      0.336

      Reljic [29]

      2007

      Caucasian

      40

      44

      9

      27

      34

      4

      0.114

      Inoue [30]

      2008

      Asian

      239

      120

      21

      393

      226

      43

      0.178

      Kotsopoulos [31]

      2008

      Caucasian

      383

      421

      140

      252

      341

      87

      0.087

      Suzuki [32]

      2008

      Asian

      150

      220

      84

      338

      425

      146

      0.522

      Cheng [33]

      2008

      Asian

      185

      133

      31

      268

      221

      41

      0.624

      Langsenlehner [34]

      2008

      Caucasian

      51

      43

      11

      40

      48

      17

      0.685

      Ericson [35]

      2009

      Caucasian

      255

      235

      50

      531

      452

      91

      0.707

      Gao [36]

      2009

      Asian

      202

      305

      117

      235

      301

      88

      0.592

      Ma [37]

      2009

      Asian

      124

      183

      81

      115

      188

      84

      0.663

      Platek [38]

      2009

      Mixed

      429

      446

      119

      788

      795

      219

      0.398

      Henrı′quez-Herna′ndez [39]

      2009

      Caucasian

      52

      65

      18

      107

      138

      47

      0.823

      Cam [40]

      2009

      Caucasian

      48

      49

      13

      47

      42

      6

      0.398

      Maruti [41]

      2009

      Mixed

      133

      139

      46

      301

      284

      62

      0.672

      Ma [42]

      2009

      Mixed

      225

      188

      45

      222

      187

      49

      0.309

      Li [43]

      2009

      Asian

      38

      17

      10

      90

      50

      3

      0.187

      Yuan [44]

      2009

      Asian

      16

      35

      29

      32

      35

      13

      0.516

      Jin [45]

      2009

      Asian

      18

      20

      3

      49

      41

      10

      0.742

      Bentley [46]

      2010

      Caucasian

      346

      402

      191

      429

      529

      205

      0.060

      Alshatwi [47]

      2010

      Asian

      34

      50

      16

      36

      49

      15

      0.800

      Sangrajrang [48]

      2010

      Asian

      410

      144

      9

      366

      110

      11

      0.427

      Weiner [49]

      2010

      Caucasian

      399

      364

      74

      386

      326

      66

      0.808

      Prasad [50]

      2011

      Asian

      124

      5

      1

      116

      8

      1

      0.062

      Batschauer [51]

      2011

      Caucasian

      27

      34

      7

      42

      34

      9

      0.593

      Mohammad [52]

      2011

      Asian

      168

      53

      1

      198

      37

      0

      0.190

      Naushad [53]

      2011

      Asian

      185

      56

      3

      205

      39

      0

      0.175

      Cerne [54]

      2011

      Caucasian

      222

      238

      62

      108

      124

      37

      0.882

      Akram [55]

      2012

      Caucasian

      65

      25

      20

      55

      45

      10

      0.855

      Barbosa [56]

      2012

      Mixed

      76

      83

      17

      87

      70

      19

      0.389

      Lajin [57]

      2012

      Caucasian

      44

      52

      23

      65

      48

      13

      0.359

      Jakubowska [58]

      2012

      Mixed

      2032

      2166

      580

      1447

      1481

      422

      0.156

      HWE Hardy–Weinberg equilibrium.

      Meta-analysis results

      Overall, there was statistically significant difference in BC risk between the patients with Ala/Ala genotype and those with Val/Val genotype (OR=0.870, 95%CI=0.789-0.958, P=0.005; Figure 1). Similarly, significant associations were also found in the recessive model comparison (OR=0.944, 95%CI=0.898-0.993, P=0.026; Table 2) and dominant model comparison (OR=0.882, 95%CI=0.808-0.963, P=0.005; Table 2). Moreover, we found significant association between Ala222Val polymorphism and BC when examining the contrast of Ala versus Val (OR=0.935, 95%CI=0.887-0.986, P=0.013; Figure 2). In the stratified analysis by ethnicity, there was significant association between Ala222Val polymorphism and BC risk for Ala/Ala vs Val/Val comparison (OR=0.787, 95%CI=0.645-0.961, P=0.019; Figure 3), recessive model comparison (OR=0.890, 95%CI=0.799-0.991, P=0.034; Table 2), dominant model comparison (OR=0.826, 95%CI=0.703-0.972, P=0.021; Table 2) and Ala allele versus Val allele comparison (OR=0.877, 95%CI=0.801-0.960, P=0.008; Figure 4) among Asian populations. For Caucasian and Mixed populations, there was no significant association between Ala222Val polymorphism and breast cancer risk (Table 2).
      http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-7-171/MediaObjects/13000_2012_659_Fig1_HTML.jpg
      Figure 1

      Forest plot of overall breast cancer risk associated with the MTHFR Ala222Val polymorphism (Ala/Ala versus Val/Val).

      Table 2

      Main results of pooled odds ratios (ORs) with confidence interval (CI) in the meta-analysis

      Variables

      No. of studies

       

      Ala/Ala vs Val/Val

        

      Ala/Ala vs Ala/Val

        

      Ala/Val vs Val/Val

       

      OR (95% CI)

      Ph

      P

      OR (95% CI)

      Ph

      P

      OR (95% CI)

      Ph

      P

      Total

      51

      0.870(0.789 0.958)

      0.001

      0.005

      0.969(0.923 1.016)

      0.206

      0.191

      0.895(0.821 0.976)

      0.021

      0.012

      Asian

      19

      0.787(0.645 0.961)

      0.017

      0.019

      0.929(0.843 1.023)

      0.212

      0.132

      0.865(0.753 0.993)

      0.300

      0.039

      Caucasian

      25

      0.869(0.741 1.020)

      0.040

      0.319

      1.004(0.921 1.095)

      0.137

      0.926

      0.910(0.778 1.064)

      0.031

      0.238

      Mixed

      7

      0.925(0.793 1.079)

      0.050

      0.087

      0.958(0.898 1.022)

      0.946

      0.191

      0.912(0.778 1.068)

      0.050

      0.253

      Variables

      No. of studies

      Ala/Val + Ala/Val vs Val/Va (dominant)

      Ala/Ala vs Ala/Val + Val/Va (recessive)

      Ala allele vs Val allele

      OR (95% CI)

      P h

      P

      OR (95% CI)

      P h

      P

      OR (95% CI)

      P h

      P

      Total

      51

      0.882(0.808 0.963)

      0.004

      0.005

      0.944(0.898 0.993)

      0.055

      0.026

      0.935(0.887 0.986)

      0.000

      0.013

      Asian

      19

      0.826(0.703 0.972)

      0.075

      0.021

      0.890(0.799 0.991)

      0.043

      0.034

      0.877(0.801 0.960)

      0.003

      0.008

      Caucasian

      25

      0.916(0.790 1.063)

      0.030

      0.247

      0.985(0.908 1.069)

      0.141

      0.720

      0.883(0.805 0.968)

      0.052

      0.359

      Mixed

      7

      0.888(0.758 1.041)

      0.029

      0.144

      0.946(0.890 1.006)

      0.773

      0.076

      0.957(0.838 1.094)

      0.000

      0.523

      Ph: P value of Q-test for heterogeneity test.

      http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-7-171/MediaObjects/13000_2012_659_Fig2_HTML.jpg
      Figure 2

      Forest plot of overall breast cancer risk associated with the MTHFR Ala222Val polymorphism (Ala-allele versus Ala-allele).

      http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-7-171/MediaObjects/13000_2012_659_Fig3_HTML.jpg
      Figure 3

      Forest plot of a meta-analysis of the association between the MTHFR Ala222Val polymorphism and breast cancer susceptibility in Asians (Ala/Ala versus Val/Val).

      http://static-content.springer.com/image/art%3A10.1186%2F1746-1596-7-171/MediaObjects/13000_2012_659_Fig4_HTML.jpg
      Figure 4

      Forest plot of a meta-analysis of the association between the MTHFR Ala222Val polymorphism and breast cancer susceptibility in Asians (Ala-allele versus Ala-allele).

      Sensitivity analysis

      In order to compare the difference and evaluate the sensitivity of the meta-analyses, we conducted one-way sensitivity analysis to evaluate the stability of the meta-analysis. The statistical significance of the results was not altered when any single study was omitted, confirming the stability of the results. Hence, results of the sensitivity analysis suggest that the data in this meta-analysis are relatively stable and credible.

      Publication bias

      Begg’s funnel plot and Egger’s test were performed to assess the publication bias. The shape of funnel plots did not reveal any evidence of obvious asymmetry in all comparison models, and the Egger’s test was used to provide statistical evidence of funnel plot symmetry. The results of Begg’s test did not show any evidence of publication bias.

      Discussion

      Breast cancer is currently the most frequently occurring cancer and the leading causes of cancer-related death among women in the world. Single nucleotide polymorphism (SNP) is the most common form of human genetic variation, and may contribute to individual’s susceptibility to cancer, however, the underlying molecular mechanism is unknown. Previous study suggested that some variants, especially those in the promoter regions of genes, may affect either the expression or activity levels of enzymes [5961] and therefore may be mechanistically associated with cancer risk. Previous studies on the relationship between MTHFR Ala222Val polymorphisms and BC risk were contradictory. These inconsistent results are possibly because of a small effect of the polymorphism on BC risk or the relatively low statistical power of the published studies. Hence, the meta-analysis was needed to provide a quantitative approach for combining the results of various studies with the same topic, and for estimating and explaining their diversity.

      Meta analysis has great power for elucidating genetic factors in cancer. On the bases of the character of cancer, the effect of one genetic component on the development of the disease can be easily masked by other genetic and environmental factors. A meta-analysis potentially investigates a large number of individuals and can estimate the effect of a genetic factor on the risk of the disease [62, 63]. The present study included data from 51 association studies that had investigated the relationship between the MTHFR Ala222Val polymorphism and BC.

      This present meta-analysis, including 20,907 cases and 23,905 controls, concerned the Ala222Val polymorphism of MTHFR gene and BC risk. In the meta-analysis, we found that the variant genotypes of the MTHFR Ala222Val polymorphisms were significantly associated with BC risk. Simultaneously, the same results presented in stratified analysis by ethnicity. We found that the variant genotype of the MTHFR Ala222Val polymorphism, in Asian populations, was associated with significant increase in BC risk. Although the MTHFR Ala222Val polymorphism may be associated with DNA repair activity, no significant association of the variant genotype with BC risk was found in Caucasian and Mixed populations, suggesting the influence of the genetic variant may be masked by the presence of other as-yet unidentified causal genes involved in colorectal cancer.

      Some limitations of this meta-analysis should be acknowledged. First, our result was based on unadjusted estimates, while a more precise analysis should be conducted adjusted by other factors like diet habit, smoking, drinking status, environmental factors and so on. Second, in the subgroup analyses by ethnicity, relatively limited study numbers to perform ethnic subgroup analysis of mixed populations. Moreover, there are no American and African-American descent populations. Thus, additional studies are warranted to evaluate the effect of this functional polymorphism on BC risk in different ethnicities, especially in American, African-American and Mixed populations. In addition, our analysis did not consider the possibility of gene-gene or SNP-SNP interactions or the possibility of linkage disequilibrium between polymorphisms.

      Despite of some limitations, this meta-analysis provided evidence of the association between the MTHFR Ala222Val polymorphisms and BC risk, supporting the hypothesis that MTHFR Ala222Val polymorphism contributes to overall BC risk. In subgroup analysis, the same results were found in Asian populations. In order to verify our findings, well-designed studies including different ethnic groups with a careful matching between cases and controls should be considered in future association studies to confirm the results from our meta-analysis. Moreover, further evaluating the effect of gene-gene and gene-environment interactions on the Ala222Val polymorphism and BC risk are necessary.

      Abbreviations

      BC: 

      Breast cancer

      HWE: 

      Hardy–Weinberg equilibrium

      OR: 

      Odds ratio

      CI: 

      Confidence interval

      MTHFR: 

      Methylenetetrahydrofolate reductase.

      Declarations

      Acknowledgements

      This work was not supported by any kind of fund.

      Authors’ Affiliations

      (1)
      Department of General Surgery, the Secondary Hospital of Tianjin Medical University

      References

      1. Hankinson SE, Colditz GA, Willett WC: Towards an integrated mod breast cancer etiology. The lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res 2004, 6:213–218.PubMedView Article
      2. Umitrescu RG, Cotarla I: Understanding breast cancer risk—where do we stand in 2005. J Cell Mol Med 2005, 9:208–221.View Article
      3. Rosenberg N, Murata M, Ikeda Y, Opare-Sem O, Zivelin A, Geffen E, Seligsohn U: The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in Whites, Japanese, and Africans. Am J Hum Genet 2002, 70:758–762.PubMedView Article
      4. Vander Put NM: A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects. Am J Hum Genet 1998, 62:1044–1051.View Article
      5. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, Den Heijer M, Kluijtmans LA, Van den Heuvel LP: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995, 10:111–113.PubMedView Article
      6. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959, 22:719–748.PubMed
      7. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986, 7:177–188.PubMedView Article
      8. Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, Baird JO, Haites NE, Heys SD, Grubb DA: Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett 2002, 181:65–71.PubMedView Article
      9. Campbell IG, Baxter SW, Eccles DM, Choong DY: Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res 2002,4(6):R14.PubMedView Article
      10. Semenza JC, Delfino RJ, Ziogas A, Anton-Culver H: Breast cancer risk and methylenetetrahydrofolate reductase polymorphism. Breast Cancer Res Treat 2003, 77:217–223.PubMedView Article
      11. Langsenlehner U, Krippl P, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Weitzer W, Samonigg H: The common 677C>T gene polymorphism of methylenetetrahy- drofolate reductase gene is not associated with breast cancer risk. Breast Cancer Res Treat 2003, 81:169–172.PubMedView Article
      12. Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Santella RM: One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res 2005, 65:1606–1614.PubMedView Article
      13. Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hebert JR, Jin F, Zheng W: MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 2004, 13:190–196.PubMedView Article
      14. Forsti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, Pamula J, Pekala W, Zientek H, Hemminki K, Kumar R: Single nucleotide polymorphisms in breast cancer. Oncol Rep 2004, 11:917–922.PubMed
      15. Lee SA, Kang D, Nishio H, Lee MJ, Kim DH, Han W, Yoo KY, Ahn SH, Choe KJ, Hirvonen A, Noh DY: Methylenete-trahydrofolate reductase polymorphism, diet, and breast cancer in Korean women. Exp Mol Med 2004, 36:116–121.PubMed
      16. Grieu F, Powell B, Beilby J, Iacopetta B: Methylenete-Trahydrofolate reductase and thymidylate synthase polymorphisms are not associated with breast cancer risk or phenotype. Anticancer Res 2004, 24:3215–3219.PubMed
      17. Lin WY, Chou YC, Wu MH, Huang HB, Jeng YL, Wu CC, Yu CP, Yu JC, You SL, Chu TY, Chen CJ, Sun CA: The MTHFR C677T polymorphism, estrogen exposure and breast cancer risk: a nested case–control study in Taiwan. Anticancer Res 2004, 24:3863–3868.PubMed
      18. Qi J, Miao XP, Tan W, Yu CY, Liang G, Lu WF, Lin DX: Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of breast cancer. Chin J Oncol 2004, 26:287–289.
      19. Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, Baisch C, Vollmert C, Illig T, Bruning T, Ko Y, Brauch H: One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomark Prev 2005, 14:3015–3018.View Article
      20. Kalemi TG, Lambropoulos AF, Gueorguiev M, Chrisafi S, Papazisis KT, Kotsis A: The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece. Cancer Lett 2005, 222:57–65.PubMedView Article
      21. Deligezer U, Akisik EE, Dalay N: Homozygosity at the C677T of the MTHFR gene is associated with increased breast cancer risk in the Turkish population. In Vivo 2005, 19:889–893.PubMed
      22. Ergul E, Sazci A, Utkan Z, Canturk NZ: Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol 2003, 24:286–290.PubMedView Article
      23. Chou YC, Wu MH, Yu JC, Lee MS, Yang T, Shih HL, Wu TY, Sun CA: Genetic polymorphisms of the methylenete-trahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case–control study in Taiwan. Carcinogenesis 2006, 27:2295–2300.PubMedView Article
      24. Kalyankumar C, Jamil K: Methylene tetrahydofolate reductase (MTHFR) C677T and A1298C polymorphisms and breast cancer in South Indian population. Int J Cancer Res 2006, 2:143–151.View Article
      25. Xu X, Gammon MD, Zhang H, Wetmur JG, Rao M, Teitelbaum SL, Britton JA, Neugut AI, Santella RM, Chen J: Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis 2007, 28:1504–1509.PubMedView Article
      26. Hekim N, Ergen A, Yaylim I, Yilmaz H, Zeybek U, Ozturk O, Isbir T: No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 2007, 25:115–117.PubMedView Article
      27. Macis D, Maisonneuve P, Johansson H, Bonanni B, Botteri E, Iodice S, Santillo B, Penco S, Gucciardo G, D’Aiuto G, Rosselli Del Turco M, Amadori M, Costa A, Decensi A: Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case–control study and a pooled meta-analysis. Breast Cancer Res Treat 2007, 106:263–271.PubMedView Article
      28. Yu CP, Wu MH, Chou YC, Yang T, You SL, Chen CJ, Sun CA: Breast cancer risk associated with multigenotypic poly-Morphisms in folate-metabolizing genes: a nested case–control study in Taiwan. Anticancer Res 2007, 27:1727–1732.PubMed
      29. Reljic A, Simundic AM, Topic E, Nikolac N, Justinic D, Stefanovic M: The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: the Croatian case–control study. Clin Biochem 2007, 40:981–985.PubMedView Article
      30. Inoue M, Robien K, Wang R, Van Den Berg DJ, Koh WP, Yu MC: Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis 2008, 29:1967–1972.PubMedView Article
      31. Kotsopoulos J, Zhang WW, Zhang S, McCready D, Trudeau M, Zhang P, Sun P, Narod SA: Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat 2008, 112:585–593.PubMedView Article
      32. Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K: One-carbon metab-olism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 2008, 2:356–362.
      33. Cheng CW, Yu JC, Huang CS, Shieh JC, Fu YP, Wang HW, Wu PE, Shen CY: Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat 2008, 111:145–155.PubMedView Article
      34. Langsenlehner T, Renner W, Yazdani-Biuki B, Langsenlehner U: Methylenetetrahydrofolatereductase (MTHFR) and breast cancer risk: a nested-case–control study and a pooled meta-analysis. Breast Cancer Res Treat 2008, 107:459–460.PubMedView Article
      35. Ericson U, Sonestedt E, Ivarsson MI, Gullberg B, Carlson J, Olsson H, Wirfalt E: Folate intake, methylenetetrahydrofolate reductase polymorphisms, and breast cancer risk in women from the Malmo¨ Diet and Cancer cohort. Cancer Epidemiol Biomarkers Prev 2009, 18:1101–1110.PubMedView Article
      36. Gao CM, Tang JH, Cao HX, Ding JH, Wu JZ, Wang J, Liu YT, Li SP, Su P, Matsuo K, Takezaki T, Tajima K: MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women. J Hum Genet 2009, 54:414–418.PubMedView Article
      37. Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S: Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case–control study in Japan. Nutr Cancer 2009, 61:447–456.PubMedView Article
      38. Platek ME, Shields PG, Marian C, McCann SE, Bonner MR, Nie J, Ambrosone CB, Millen AE, Ochs-Balcom HM, Quick SK, et al.: Alcohol consumption and genetic variation in Methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate homocysteine methyltransferase in relation to breast cancer risk. Cancer Epidemiol Biomark Prev 2009, 18:2453–2459.View Article
      39. Henrıquez-Hernandez LA, Murias-Rosales A, Hernandez Gon-zalez A, Cabrera De Leon A, Dıaz-Chico BN, Mori De Santiago M, Fernandez Perez L: Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: a case–control study. Oncol Rep 2009, 22:1425–1433.PubMed
      40. Cam R, Eroglu A, Egin Y, Akar N: Dihydrofolate reduc-Tase (DHRF) 19-bp intron-1 deletion and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms in breast cancer. Breast Cancer Res Treat 2009, 115:431–432.PubMedView Article
      41. Maruti SS, Ulrich CM, Jupe ER, White E: MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case–control study. Breast Cancer Res 2009, 11:R91.PubMedView Article
      42. Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola J Jr, Laginha FM, Tsugane S: Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case–control study in Brazilian women. BMC Cancer 2009, 9:122.PubMedView Article
      43. Li WD, Chen SQ: Association of methylenetetrahydrofolate reductase C677T polymorphism and breast cancer risk. J Prac Med 2009, 25:2031–2033.
      44. Yuan H, Xu XY, Wang ZL: The relation between polymorphisms of methylenetetrahydrofolate reductase C677T and the risk of breast cancer. J MuDanJiang Med Univ 2009, 30:2–4.
      45. Jin ZZ, Lu Q, Ge DH, Zong M, Zhu QH: Effect of the methylenetetrahydrofolate reductase gene C677T polymorphism on C-erbB-2 methylation status and its association with cancer. Mol Med Rep 2009, 2:283–289.View Article
      46. Bentley AR, Raiszadeh F, Stover PJ, Hunter DJ, Hankinson SE, Cassano PA: No association between cSHMT genotypes and the risk of breast cancer in the Nurses’ Health Study. Eur J Clin Nutr 2010, 64:108–110.PubMedView Article
      47. Alshatwi AA: Breast cancer risk, dietary intake, and methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms. Food Chem Toxicol 2010, 48:881–1885.
      48. Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, Yoshida T: Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case–control study in Thai women. Breast Cancer Res Treat 2010, 123:885–893.PubMedView Article
      49. Weiner AS, Boyarskih UA, Voronina EN, Selezneva IA, Sinkina TV, Lazarev AF, Petrova VD, Filipenko ML: Polymorphic Variants of Folate Metabolizing Genes (C677T and A1298C MTHFR and C1420T SHMT1 and G1958A MTHFD) are Not Associated with the Risk of Breast Cancer in the West Siberian Region of Russia. Mol Biol 2010,44(5):720–727.View Article
      50. Vidudala V.T.S. Prasad Harpreet Wilkhoo: Association of the Functional Polymorphism C677T in the Methylenetetrahydrofolate Reductase Gene with Colorectal, Thyroid, Breast, Ovarian, and Cervical Cancers. Onkologie 2011, 34:422–426.View Article
      51. Batschauer AP, Cruz NG, Oliveira VC, Coelho FF, Santos IR, Alves MT, Fernandes AP, Carvalho MG, Gomes KB: HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women. Mol Cell Biochem 2011, 357:247–253.PubMedView Article
      52. Mohammad NS, Rupasree Y, Addepalli P, Gottumukkala SR, Digumarti RR, Kutala VK: Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer. Mol Cell Biochem 2011, 349:159–167.PubMedView Article
      53. Mohammad NS, Addepalli P, Digumarti RR, Gottumukkala SR, Kutala VK: Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer. Mol Biol Rep 2011, 38:4893–4901.View Article
      54. Ja SMina Ziva C, Vida STG, KSeniJa GSK, Kovic SJn: Lack of association between methylenetetrahydrofolate reductase genetic polymorphisms and postmenopausal breast cancer risk. Molecular Medicine Reports 2011, 4:175–179.
      55. Muhammad A, Malik FA, Mahmood Akhtar K: Mutational Analysis of the MTHFR Gene in Breast Cancer Patients of Pakistani Population. Asian Pacific J Cancer Pre 2012, 13:1599–1603.View Article
      56. de Cassia Carvalho Barbosa R, Debora Costa M, Thiago Fernando Vasconcelos F, Diogo Campos S, Victor Hugo Medeiros A, Silvia Helena Barem R: Associations of polymorphisms of folate cycle enzymes and risk of breast cancer in a Brazilian population are age dependent. Mol Biol Rep 2012, 39:4899–4907.View Article
      57. Lajin B, Sakur AA, Ghabreau L, Alachkar A: Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women. Tumor Biol 2012, 33:1133–1139.View Article
      58. Jakubowska A, Rozkrut D, Antoniou A, et al.: Association of PHB 1630 C4T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study. British Journal of Cancer 2012, 106:2016–2024.PubMedView Article
      59. Skoog T, Van't Hooft FM, Kallin B, Jovinge S, Boquist S, Nilsson J, Eriksson P, Hamsten A: A common functional polymorphism (C-->A substitution at position −863) in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet 1999, 8:1443–1449.PubMedView Article
      60. Momparler RL, Bovenzi V: DNA methylation and cancer. J Cell Physiol 2000, 183:145–154.PubMedView Article
      61. Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q: A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res 2002, 62:4992–4995.PubMed
      62. Fujisawa T, Ikegami H, Kawaguchi Y: Meta-analysis of association of insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy. Diabetologia 1998,41(1):47–53.PubMedView Article
      63. Liwei L, Chunyu L, Ruifa H: Association between manganese superoxide dismutase gene polymorphism and risk of prostate cancer: a meta-analysis. Urology 2009,74(4):884–888.PubMedView Article

      Copyright

      © Yu and Chen; licensee BioMed Central Ltd. 2012

      This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

      Advertisement